[3,4-a:3,4-c]carbazole compounds

ABSTRACT

A compound selected from those of formula (I):  
                 
 
     wherein:  
     W 1  represents, together with carbon to which it is bonded, phenyl, pyridyl,  
     Z represents a group of formula U—V as defined in the description,  
     Q 1  represents oxygen, NR 2  as defined in the description,  
     Q 2  represents oxygen, NR′ 2  as defined in the description,  
     X 1 , X 2 , X′ 1  and X′ 2  each represents hydrogen, hydroxy, alkoxy, mercapto or alkylthio,  
     Y 1 , Y 2 , Y′ 1  and Y′ 2  each represents hydrogen,  
     or X 1  and Y 1 , X 2  and Y 2 , X′ 1  and Y′ 1 , X′ 2  and Y′ 2  with carbon carrying them, together form carbonyl or thiocarbonyl,  
     R 1  is as defined in the description, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same which are useful in the treatment of cancer.

FIELD OF THE INVENTION

[0001] The needs of anti-cancer therapy call for the constantdevelopment of new anti-proliferative agents, with the aim of obtainingmedicaments that are both more active and better tolerated. Thecompounds of the present invention exhibit in particular anti-tumourproperties, which accordingly render them useful in the treatment ofcancers. Among the types of cancer that can be treated with thecompounds of the present invention there may be mentioned, withoutimplying any limitation, adenocarcinomas and carcinomas, sarcomas,gliomas and leukaemias. By virtue of their properties, the compounds ofthe invention can advantageously be associated with all cytotoxictreatments currently in use, as well as with radiotherapies, whosetoxicity is not increased thereby, and with the various hormonetherapies directed against cancers (blood and prostate).

DESCRIPTION OF THE PRIOR ART

[0002] The Patent Applications WO 95/07910 and WO 96/04906 describeindole compounds and claim them, on the one hand, for their antiviralactivity and, on the other hand, for the treatment and prevention ofrestenosis. The Patent Applications WO 00/47583, WO 97/21677 and WO96/11933 disclose cyclopenta[g]pyrrolo[3,4-e]indole compounds which arefused on the indole moiety and the cyclopentene moiety of the compoundsto an aromatic or non-aromatic ring system and which optionally containhetero atoms. Those compounds exhibit pharmacological properties thatrender them useful especially in the treatment of cancer. PatentApplication WO 01/85686 describes pyrrolo[3,4-c]carbazole compounds foruse in the treatment of neurodegenerative diseases, inflammation,ischaemia and cancer. Patent Application WO 02/24699 describestetrahydrocarbazole compounds for use on the one hand in antimicrobialtreatment and on the other hand as a deodorant and disinfectant of theskin.

DETAILED DESCRIPTION OF THE INVENTION

[0003] The present invention relates more especially to compounds offormula (I):

[0004] wherein:

[0005] A represents a saturated or partially or fully unsaturated ring,wherein the unsaturation optionally confers an aromatic nature on thering,

[0006] W₁, together with the carbon atoms to which it is bonded,represents a phenyl group or a pyridyl group,

[0007] Z represents one or more identical or different groups of formulaU—V wherein:

[0008] U represents a single bond, a linear or branched (C₁-C₆)alkylenechain or a linear or branched (C₂-C₆)allkenyl chain optionallysubstituted by one or more identical or different groups selected fromhalogen and hydroxy, and/or optionally containing one or moreunsaturated bonds,

[0009] V represents a group selected from a hydrogen atom, a halogenatom and the groups cyano, nitro, azido, linear or branched(C₁-C₆)alkyl, aryl, aryl-(C₁-C₆)alkyl in which the alkyl moiety may belinear or branched, hydroxy, linear or branched (C₁-C₆)alkoxy, aryloxy,aryl-(C₁-C₆)alkoxy in which the alkoxy moiety may be linear or branched,formyl, carboxy, aminocarbonyl, NR₃R₄, —C(O)—T₁, —C(O)—NR₃—T₁,—NR₃—C(O)—T₁, —O—C(O)—T₁, —C(O)—O—T₁, —NR₃—T₂—NR₃R₄, —NR₃—T₂—OR₃,—NR₃—T₂—CO₂R₃, —O—T′₂—NR₃R₄, —O—T′₂—OR₃, —O—T′₂—CO₂R₃, and —S(O)_(t)—R₃,

[0010]  wherein

[0011] R₃ and R₄, which may be indentical or different, each representsa group selected from a hydrogen atom and the groups linear or branched(C₁-C₆)alkyl, aryl, and aryl-(C₁-C₆)alkyl in which the alkyl moiety maybe linear or branched, or R₃+R₄, with the nitrogen atom carrying them,together form a saturated monocyclic or bicyclic heterocycle that hasfrom 5 to 10 ring atoms, optionally contains in the ring system a secondhetero atom selected from oxygen and nitrogen, and is optionallysubstituted by a group selected from linear or branched (C₁-C₆)alkyl,aryl, aryl-(C₁-C₆)alkyl in which the alkyl moiety may be linear orbranched, hydroxy, linear or branched (C₁-C₆)alkoxy, amino, linear orbranched mono-(C₁-C₆)alkylamino, and di(C₁-C₆)alkylamino in which thealkyl moieties may be linear or branched,

[0012] T₁ represents a group selected from linear or branched(C₁-C₆)alkyl that is optionally substituted by a group selected from—OR₃, —NR₃R₄, —CO₂R₃, —C(O)R₃ and —C(O)NR₃R₄ wherein R₃ and R₄ are asdefined hereinbefore; aryl, and aryl-(C₁-C₆)alkyl in which the alkylmoiety may be linear or branched; or T₁ represents a linear or branched(C₂-C₆)alkenyl chain optionally substituted by a group selected from—OR₃, —NR₃R₄, —CO₂R₃, —C(O)R₃ and —C(O)NR₃R₄ wherein R₃ and R₄ are asdefined hereinbefore,

[0013] T₂ represents a linear or branched (C₁-C₆)alkylene chain,

[0014] T′₂ represents a linear or branched (C₁-C₆)alkylene chainoptionally substituted with one ore more hydroxy groups,

[0015] t represents an integer of from 0 to 2 inclusive,

[0016]  or Z represents a group selected from methylenedioxy orethylenedioxy,

[0017] Q₁ represents a group selected from an oxygen atom and an NR₂group, wherein R₂ represents a group selected from a hydrogen atom andthe groups linear or branched (C₁-C₆)alkyl, aryl, aryl-(C₁-C₆)alkyl inwhich the alkyl moiety may be linear or branched, cycloalkyl,cycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety may be linear orbranched, —OR₃, —NR₃R₄, —O—T₂—NR₃R₄, —NR₃—T₂—NR₃R₄, linear or branched(C₁-C₆)hydroxyalkylamino, di((C₁-C₆)hydroxyalkyl)amino in which thealkyl moieties may be linear or branched, —C(O)—R₃ and —NH—C(O)—R₃; orR₂ represents a linear or branched (C₁-C₆)alkylene chain substituted byone or more identical or different groups selected from halogen atomsand the groups cyano, nitro, —OR₃, —NR₃R₄, —CO₂R₃, —C(O)R₃, linear orbranched (C₁-C₆)hydroxyalkylamino, di((C₁-C₆)hydroxyalkyl)amino in whichthe alkyl moieties may be linear or branched, and —C(O)—NHR₃, the groupsR₃, R₄ and T₂ being as defined hereinbefore,

[0018] Q₂ represents a group selected from an oxygen atom and an NR′₂group wherein R′₂ represents a group selected from a hydrogen atom andthe groups linear or branched (C₁-C₆)alkyl, aryl, aryl-(C₁-C₆)alkyl inwhich the alkyl moiety may be linear or branched, cycloalkyl,cycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety may be linear orbranched, —OR₃, —NR₃R₄, —O—T₂NR₃—R₄, —NR₃—T₂—NR₃R₄, linear or branched(C₁-C₆)hydroxyalkylamino, di((C₁-C₆)hydroxyalkyl)amino in which thealkyl moieties may be linear or branched, —C(O)—R₃ and —NH—C(O)—R₃; orR′₂ represents a linear or branched. (C₁-C₆)alkylene chain substitutedby one or more identical or different groups selected from halogen atomsand the groups cyano, nitro, —OR₃, —NR₃R₄, —CO₂R₃, —C(O)R₃, linear orbranched (C₁-C₆)hydroxyalkylamino, di((C₁-C₆)-hydroxyalkyl)amino inwhich the alkyl moieties may be linear or branched, and —C(O)—NHR₃, thegroups R₃, R₄ and T₂ being as defined hereinbefore,

[0019] X₁ represents a group selected from a hydrogen atom and thegroups hydroxy, linear or branched (C₁-C₆)alkoxy, mercapto, and linearor branched (C₁-C₆)alkylthio,

[0020] Y₁ represents a hydrogen atom, or

[0021] X₁ and Y₁, with the carbon atom carrying them, together form acarbonyl or thiocarbonyl group,

[0022] X₂ represents a group selected from a hydrogen atom and thegroups hydroxy, linear or branched (C₁-C₆)alkoxy, mercapto and linear orbranched (C₁-C₆)alkylthio,

[0023] Y₂ represents a hydrogen atom, or

[0024] X₂ and Y₂, with the carbon atom carrying them, together form acarbonyl or thiocarbonyl group,

[0025] X′₁ represents a group selected from a hydrogen atom and thegroups hydroxy, linear or branched (C₁-C₆)alkoxy, mercapto and linear orbranched (C₁-C₆)alkylthio,

[0026] Y′₁ represents a hydrogen atom, or

[0027] X′₁ and Y′₁, with the carbon atom carrying them, together form acarbonyl or thiocarbonyl group,

[0028] X′₂ represents a group selected from a hydrogen atom and thegroups hydroxy, linear or branched (C₁-C₆)alkoxy, mercapto and linear orbranched (C₁-C₆)alkylthio,

[0029] Y′₂ represents a hydrogen atom, or

[0030] X′₂ and Y′₂, with the carbon atom carrying them, together form acarbonyl or thiocarbonyl group,

[0031] R₁ represents a group selected from a hydrogen atom and a linearor branched (C₁-C₆)alkyl group that is optionally substituted by one ormore groups selected from hydroxy, linear or branched (C₁-C₆)alkoxy,linear or branched (C₁-C₆)hydroxyalkoxy or NR₃R₄, the groups R₃ and R₄being as defined hereinbefore; or R₁ represents a group of formula (a):

[0032]  wherein:

[0033] R_(a), R_(b), R_(c) and R_(d), which may be identical ordifferent, each represents, independently of the others, a bond or agroup selected from a hydrogen atom, a halogen atom, and the groupshydroxy, linear or branched (C₁-C₆)alkoxy, aryloxy, aryl-(C₁-C₆)alkoxyin which the alkoxy moiety may be linear or branched, linear or branched(C₁-C₆)alkyl, aryl-(C₁-C₆)alkyl in which the alkyl moiety may be linearor branched, aryl, —NR₃R₄ wherein R₃ and R₄ are as defined hereinbefore,azido, —N═NR₃ (wherein R₃ is as defined hereinbefore), and —O—C(O)—R₅wherein R₅ represents a linear or branched (C₁-C₆)alkyl group(optionally substituted by one or more groups selected from halogen,hydroxy, amino, linear or branched (C₁-C₆)-alkylamino, anddi(C₁-C₆)alkylamino in which the alkyl moieties may be linear orbranched); or R₅ represents aryl, aryl-(C₁-C₆)alkyl in which the alkylmoiety may be linear or branched, cycloalkyl or heterocycloalkyl,

[0034] R_(e) represents a methylene group (H₂C═) or a group of formula—U—R_(a) wherein U₁ represents a single bond or a methylene group andR_(a) is as defined hereinbefore,

[0035] n is 0 or 1,

[0036] it being understood that the group of formula (a) is bonded tothe nitrogen atom by R_(a), R_(b), R_(c), R_(d) or R_(e),

[0037] to their enantiomers, diastereoisomers, and also to additionsalts thereof with a pharmaceutically acceptable acid or base,

[0038] with the proviso that the compounds of formula (I) are other thanthe following compounds:

[0039]3b,6a,6b,7-tetrahydro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,3aH,5H,5H)-tetrone;

[0040]5-ethyl-3b,6a,6b,7-tetrahydro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,3aH,5H)-tetrone;

[0041]3b,6a,7,11c-tetrahydro-1H-dipyrrolo[3,4-a:3,4-c]carboazole-1,3,4,6-(2H,3aH,5H)-tetrone;

[0042]3b,6a,6b,7-tetrahydrofuro[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,6-(2H,3aH,5H)-tetrone;

[0043] wherein aryl is understood to mean a phenyl, naphthyl,dihydronaphthyl, tetrahydronaphthyl, indenyl or indanyl group, each ofthose groups optionally being substituted by one or more identical ordifferent groups selected from halogen, linear or branched (C₁-C₆)alkyl,linear or branched (C₁-C₆)trihaloalkyl, hydroxy, linear or branched(C₁-C₆)alkoxy, and NR₃R₄, the groups R₃ and R₄ being as definedhereinbefore.

[0044] Among the pharmaceutically acceptable acids there may bementioned, without implying any limitation, hydrochloric acid,hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid,trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinicacid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citricacid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid,etc.

[0045] Among the pharmaceutically acceptable bases there may bementioned, without implying any limitation, sodium hydroxide, potassiumhydroxide, triethylamine, tert-butylamine etc. . . .

[0046] Preferred compounds of the invention are those wherein X₁ and Y₁,with the carbon atom carrying them, together form a carbonyl group, X₂and Y₂, with the carbon atom carrying them, together form a carbonylgroup, X′₁ and Y′₁, with the carbon atom carrying them, together form acarbonyl group and X′₂ and Y′₂, with the carbon atom carrying them,together form a carbonyl group.

[0047] Advantageously, the Q₁ group preferred according to the inventionis the group —NR₂ wherein R₂ is as defined for formula (I).

[0048] Advantageously, the Q₂ group preferred according to the inventionis the group —NR′₂ wherein R′₂ is as defined for formula (I).

[0049] According to an advantageous embodiment, preferred compounds ofthe invention are compounds of formula (I) corresponding more especiallyto formula (IA):

[0050] wherein R₁, R₂, R′₂, W₁ and Z are as defined for formula (I).

[0051] According to a second advantageous embodiment, preferredcompounds of the invention are compounds of formula (I) correspondingmore especially to formula (IB):

[0052] wherein R₁, R₂, R′₂ and Z are as defined for formula (I).

[0053] According to a third advantageous embodiment, preferred compoundsof the invention are compounds of formula (I) corresponding moreespecially to formula (IC):

[0054] wherein R₁, R₂, R′₂ and Z are as defined for formula (I).

[0055] According to a fourth advantageous embodiment, preferredcompounds of the invention are compounds of formula (I) correspondingmore especially to formula (ID):

[0056] wherein R₂, R′₂, W₁, Z, R_(b), R_(c), R_(d) and R_(e) are asdefined for formula (I).

[0057] According to a fifth advantageous embodiment, preferred compoundsof the invention are compounds of formula (I) corresponding moreespecially to formula (IE):

[0058] wherein R₂, R′₂, Z, R_(b), R_(c), R_(d) and R_(e) are as definedfor formula (I).

[0059] According to a sixth advantageous embodiment, preferred compoundsof the invention are compounds of formula (I) corresponding moreespecially to formula (IF):

[0060] wherein R₂, R′₂, Z, R_(b), R_(c), R_(d) and R_(e) are as definedfor formula (I).

[0061] Preferably, the substituent Z preferred according to theinvention is a group of formula U—V wherein U represents a single bondand V represents a group selected from a hydrogen atom, a halogen atomand the groups nitro, linear or branched (C₁-C₆)alkyl, hydroxy, linearor branched (C₁-C₆)alkoxy, aryl-(C₁-C₆)alkoxy in which the alkoxy moietymay be linear or branched, and NR₃R₄ wherein R₃ and R₄ each represents ahydrogen atom.

[0062] Even more preferably, the substituent Z preferred according tothe invention is a group of formula U—V wherein U represents a singlebond and V represents a group selected from a hydrogen atom, a halogenatom and the groups hydroxy and aryl-(C₁-C₆)alkoxy in which the alkoxymoiety may be linear or branched.

[0063] In an embodiment of interest, the group R₁ preferred according tothe invention is a hydrogen atom, a linear or branched (C₁-C₆)alkylgroup or a group of formula (a):

[0064] bonded to the nitrogen atom by Ra,

[0065] wherein:

[0066] R_(b), R_(c), and R_(d) represent a hydroxy group, anaryl-(C₁-C₆)alkoxy group in which the alkoxy moiety may be linear orbranched, or a group —O—C(O)—R₅ wherein R₅ represents a linear orbranched (C₁-C₆)alkyl group,

[0067] R_(e) represents a group of formula U₁—R_(a) wherein U₁represents a methylene group and R_(a) has the same definitions asR_(b), R_(c) and R_(d) and n is 0.

[0068] In an embodiment of even greater interest, the group R₁ preferredaccording to the invention is hydrogen.

[0069] In an embodiment of interest, the groups R₂ preferred accordingto the invention are hydrogen, linear or branched (C₁-C₆)alkyl, OR₃,NR₃R₄, and a linear or branched (C₁-C₆)alkylene chain substituted by anOR₃ or NR₃R₄ group wherein R₃ and R₄ are as defined for formula (I).

[0070] In an embodiment of even greater interest, the groups R₂preferred according to the invention are hydrogen, linear or branched(C₁-C₆)alkyl, and a linear or branched (C₁-C₆)alkylene chain substitutedby an NR₃R₄ group wherein R₃ and R₄ are as defined for formula I.

[0071] In an embodiment of interest, the groups R′₂ preferred accordingto the invention are hydrogen, linear or branched (C₁-C₆)alkyl, and alinear or branched (C₁-C₆)alkylene chain substituted by an NR₃R₄ groupwherein R₃ and R₄ are as defined for formula (I).

[0072] In an embodiment of interest, the group of formula (a) preferredaccording to the invention is the glucopyranosyl group of formula:

[0073] The following are preferred compounds according to the invention:

[0074] 1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,5H,7H)-tetrone,

[0075]2-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,5H,7H)-tetrone,

[0076]2,5-dimethyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,5H,7H)-tetrone,

[0077]2-[2-(diethylamino)ethyl]-5-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,5H,7H)-tetrone,

[0078]10-hydroxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,5H,7H)-tetrone

[0079] The enantiomers, diastereoisomers, and addition salts with apharmaceutically acceptable acid or base, of the preferred compoundsform an integral part of the invention.

[0080] The present invention relates also to a process for thepreparation of compounds of formula (I), which is characterised in thatthere is used as starting material a compound of formula (II):

[0081] wherein R_(2a) represents a hydrogen atom or a methyl group andR₁, X′₁, Y′₁, X′₂, Y′₂, W₁ and Z are as defined for formula (I),

[0082] which is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinoneto yield a compound of formula (III):

[0083] wherein R₁, R_(2a), X′₁, Y′₁, X′₂, Y′₂, W₁ and Z are as definedhereinbefore, which compound of formula (III) is:

[0084] either treated with aqueous sodium hydroxide solution and thenplaced in the presence of hydrochloric acid to yield a compound offormula (IV):

[0085] wherein R₁, X′₁, Y′₁, X′₂, Y′₂, W₁ and Z are as definedhereinbefore, which compound of formula (IV) is treated with a compoundof formula (V):

[0086] wherein R′₂, X₁, Y₁, X₂ and Y₂ are as defined for formula (I) toyield a compound of formula (I/a) and (I/b), a particular case of thecompounds of formula (I):

[0087] wherein R₁, R′₂, X₁, Y₁, X₂, Y₂, X′₁, Y′₁, X′₂, Y′₂, W₁ and Z areas defined hereinbefore,

[0088] which compound(s) of formula (I/a) and/or (I/b) is(are)optionally subjected to the action of trifluoroacetic acid to yield acompound of formula (I/c), a particular case of the compounds of formula(I):

[0089] wherein R₁, R′₂, X₁, Y₁, X₂, Y₂, X′₁, Y′₁, X′₂, Y′₂, W₁ and Z areas defined hereinbefore,

[0090] the totality of the compounds of formulae (I/a), (I/b) and (I/c)constituting the compounds of formula (I/d):

[0091] wherein A, R₁, R′₂, X₁, Y₁, X₂, Y₂, X′₁, Y′₁, X′₂, Y′₂, W₁ and Zare as defined hereinbefore,

[0092] which compound of formula (I/d) is optionally subjected to theaction of a compound of formula (VII):

R_(2b)—NH₂  (VII)

[0093] wherein R_(2b) has the same definition as R₂ in formula (I), withthe exception of a hydrogen atom and a methyl group, to yield compoundsof formula (I/e), a particular case of the compounds of formula (I):

[0094] wherein A, R₁, R′₂, R_(2b), X₁, Y₁, X₂, Y₂, X′₁, Y′₁, X′₂, Y′₂,W₁ and Z are as defined hereinbefore,

[0095] or subjected in succession to the same reaction conditions as thecompounds of formulae (IV), (I/a) and (I/b) to yield a compound offormula (I/f), a particular case of the compounds of formula (I):

[0096] wherein A, R₁, R′₂, R_(2a), X₁, Y₁, X₂, Y₂, X′₁, Y′₁, X′₂, Y′₂,W₁ and Z are as defined hereinbefore,

[0097] the totality of the compounds (I/d), (I/e) and (I/f) constitutingthe compounds of formula (I/g):

[0098] wherein A, R₁, R′₂, Q₁, X₁, Y₁, X₂, Y₂, X′₁, Y′₁, X′₂, Y′₂, W₁and Z are as defined hereinbefore,

[0099] which compound of formula (I/g), when R′₂ represents a hydrogenatom or a methyl group, is optionally subjected in succession to thesame reactions conditions as the compound of formula (III) to yield acompound of formula (I/i), a particular case of the compounds of formula(I):

[0100] wherein A, R₁, Q₁, X₁, Y₁, X₂, Y₂, X′₁, Y′₁, X′₂, Y′₂, W₁ and Zare as defined hereinbefore,

[0101] which compound of formula (I/i) is optionally subjected to theaction of a compound (VIII):

R′_(2b)—NH₂  (VIII)

[0102] wherein R′_(2b) has the same definition as R′₂ in formula (I),with the exception of the definitions hydrogen atom and methyl group, toyield compounds of formula (I/j), a particular case of the compounds offormula (I):

[0103] wherein A, R₁, R′_(2b), Q₁, X₁, Y₁, X₂, Y₂, X′₁, Y′₁, X′₂, Y′₂,W₁ and Z are as defined hereinbefore,

[0104] the compounds of formulae (I/a) to (I/j) constituting thetotality of the compounds of formula (I), which, if appropriate, arepurified according to conventional purification techniques, may, ifdesired, be separated into their different isomers according to aconventional separation technique, the sub stituents R_(a), R_(b),R_(c), R_(d) and R_(e) of which may be modified according toconventional methods of organic synthesis used in the field of sugarchemistry, and which compounds, if desired, are converted into additionsalts with a pharmaceutically acceptable acid or base.

[0105] The compounds of formula (II) may advantageously be obtainedstarting from a compound of formula (A):

[0106] wherein W₁ and Z are as defined for formula (I), which isreacted:

[0107] either with a compound of formula (B):

[0108] wherein R_(2a), X′₁, Y′₁, X′₂ and Y′₂ are as definedhereinbefore, to yield a compound of formula (C):

[0109] wherein R_(2a), X′₁, Y′₁, X′₂, Y′₂, W₁ and Z are as definedhereinbefore, which compound of formula (C) is optionally subjected tothe action of a compound of formula (IX):

R_(1a)—G  (IX)

[0110] wherein G represents a hydroxy group or a leaving group andR_(1a), which is other than a hydrogen atom, has the same definition asR₁ in formula (I), to yield a compound of formula (D):

[0111] wherein R_(1a), R_(2a), X′₁, Y′₁, X′₂, Y′₂, W₁ and Z are asdefined hereinbefore,

[0112] the compounds of formulae (C) and (D) constituting the totalityof the compounds of formula (II),

[0113] or with a compound of formula (E) in the presence ofalkylmagnesium halide:

[0114] wherein R_(2a), X′₁, Y′₁, X′₂ and Y′₂ are as definedhereinbefore, to yield a compound of formula (F):

[0115] wherein R_(1a), R_(2a), X′₁, Y′₁, X′₂, Y′₂, W₁ and Z are asdefined hereinbefore, which compound of formula (F) is optionallysubjected to the same reaction conditions as the compound of formula(C), to yield a compound of formula (G):

[0116] wherein R_(1a), R_(2a), X′₁, Y′₁, X′₂, Y′₂, W₁ and Z are asdefined hereinbefore, which compound of formula (G) is hydrogenatedaccording to conventional methods of organic synthesis to yield acompound of formula (II).

[0117] The compounds of formulae (V), (VII), (VIII), (IX), (A), (B) and(E) are either commercially available products or are products obtainedaccording to conventional methods of organic synthesis well known to theperson skilled in the art.

[0118] The compounds of formula (I) exhibit anti-tumour properties thatare of particular interest. The characteristic properties of thosecompounds allow them to be used therapeutically as anti-tumour agents.

[0119] The compounds of the invention may also be used in therapeuticassociation with another anti-cancer agent, such as, for example,paclitaxel, tamoxifen and derivatives thereof, cisplatin and analoguesthereof, irinotecan and metabolites thereof, various alkylating agents,the chief of which is cyclophosphamide, etoposide, vinca alkaloids,doxorubicin and other anthracyclins, and nitrosoureas.

[0120] The present invention relates also to pharmaceutical compositionscomprising as active ingredient at least one compound of formula (I),optical isomers thereof, or an addition salt thereof with apharmaceutically acceptable acid or base, on its own or in combinationwith one or more pharmaceutically acceptable, inert, non-toxicexcipients or carriers.

[0121] Among the pharmaceutical compositions according to the inventionthere may be mentioned more especially those which are suitable fororal, parenteral (intravenous, intramuscular or subcutaneous), per- ortrans-cutaneous, nasal, rectal, perlingual, ocular or respiratoryadministration, and especially tablets or dragees, sublingual tablets,gelatin capsules, capsules, suppositories, creams, ointments, dermalgels, injectable or drinkable preparations, aerosols, eye drops and nosedrops etc.

[0122] By virtue of the pharmacological properties characteristic of thecompounds of formula (I), the pharmaceutical compositions comprising thesaid compounds of formula (I) as active ingredient are accordinglyespecially useful in the treatment of cancers.

[0123] The useful dosage varies according to the age and weight of thepatient, the administration route, the nature and the severity of thedisorder, and the administration of any associated treatments, andranges from 1 mg to 500 mg per day in one or more administrations.

[0124] The Examples that follow illustrate the invention but do notlimit in in any way. The starting materials employed are known productsor products prepared according to known procedures.

[0125] The structures of the compounds described in the Examples weredetermined according to customary spectrophotometric techniques(infrared, nuclear magnetic resonance, mass spectrometry, . . . ).

PREPARATION A3b,6a,6b,7-tetrahydro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,3aH,5H)-tetrone

[0126] Step A: 3-(1H-indol-3-yl)-2,5-pyrrolidinedione

[0127] The expected product is obtained in accordance with the processdescribed by J. Bergman et al. (Tetrahedron, 1999, 55, pp. 2363-2370).

[0128] Step B: 3-(1H-indol-3-yl)-1H-pyrrole-2,5-dione

[0129] The expected product is obtained in accordance with the processdescribed by J. Bergman et al. (Tetrahedron, 1999, 55, pp. 2363-2370).

[0130] Step C:3b,6a,6b,7-tetrahydro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,3aH,5H)-tetrone

[0131] The expected product is obtained in accordance with the processdescribed by J. Bergman et al. (J. Chem. Soc., Perkin Trans. I, 2000.pp. 2615-2621).

PREPARATION B 3-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione

[0132] Step A: 3-(1H-indol-3-yl)-1-methyl-2,5-pyrrolidinedione

[0133] The expected product is obtained in accordance with the processdescribed by J. Bergman et al. (Tetrahedron, 1999, 55, pp. 2363-2370).

[0134] Step B: 3-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione

[0135] The expected product is obtained in accordance with the processdescribed by J. Bergman et al. (Tetrahedron, 1999, 55, pp. 2363-2370).

PREPARATION C3-[5-(benzyloxy)-1H-indol-3-yl]-1-methyl-1H-pyrrole-2,5-dione

[0136] Step A:3-[5-(benzyloxy)-1H-indol-3-yl]-1-methy-2,5-pyrrolidinedione

[0137] A mixture of 5-benzyloxy-indole (8 mmol) and N-methylmaleimide (8mmol) in 8 ml of acetic acid is refluxed for 48 hours. The acetic acidis evaporated off. Purification by chromatography on silica gel (ethylacetate/cyclohexane: 2/8 to 7/3) allows the expected product to beobtained.

[0138] Melting point: 49-53° C.

[0139] IR (KBr): ν_(C═O)=1690, 1700 cm⁻¹; ν_(NH)=3300-3500 cm⁻¹.

[0140] Mass spectrum (FAB): 335.14 [M+H⁺].

[0141] Step B:3-[5-(benzyloxy)-1H-indol-3-yl]-1-methyl-1H-pyrrole-2,5-dione

[0142] A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2 mmol)in 20 ml of dioxane is slowly added to a solution of the compoundobtained in the above Step (2 mmol) in 20 ml of dioxane. The reactionmixture is stirred overnight at ambient temperature. After filtration,followed by removal of the dioxane by evaporation, the reaction mixtureis taken up in isopropanol for recrystallisation. The expected productis obtained by filtration and washing with isopropane the precipitatethat has formed.

[0143] Melting point: 176-182° C.

[0144] IR (KBr): ν_(C═O)=1690, 1700 cm⁻¹; ν_(NH)=3300-3440 cm⁻¹.

[0145] Mass spectrum (FAB): 333.12 [M+H⁺].

PREPARATION D 3-(1H-indol-3-yl)-2,5-furandione

[0146] A mixture of the compound of Preparation B (0.884 mmol) andsodium hydroxde pellets (12.5 mmol) in 100 ml of distilled water isrefluxed for 2 hours. After cooling the reaction mixture, concentratedhydrochloric acid is added dropwise until a precipitate is formed. Theexpected product is isolated by filtration of the precipitate.

[0147] Melting point: 210-214° C.

[0148] IR (KBr): ν_(C═O)=1740, 1800 cm⁻¹; ν_(NH)=3320 cm⁻¹.

PREPARATION E 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrole-2,5-dione

[0149] Step A:3-bromo-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrole-2,5-dione

[0150] A solution of ethylmagnesium bromide is prepared from magnesium(12.7 mmol) suspended in bromoethane (12.7 mmol) and dry tetrahydrofuran(5 ml). The solution is stirred for 1 hour at ambient temperature andthen 7-azaindole (12.7 mmol), dissolved in 40 ml of anhydrous toluene,is added dropwise. After 1 hour 30 minutes' stirring at ambienttemperature, a solution of 2,3-dibromomaleimide (3.53 mmol) in 40 ml ofanhydrous toluene is added dropwise. After 20 minutes, 60 ml of drydichloromethane are added, and then the reaction mixture is stirred for75 hours at 40° C. and subsequently hydrolysed with a saturated aqueousammonium chloride solution. The organic product is extracted with ethylacetate, and then the combined organic phases are dried over magnesiumsulphate and filtered. After removal of the solvent by evaporation, andpurification of the residue by chromatography on silica gel(cyclohexane/ethyl acetate: 3/2), the expected product is isolated.

[0151] Step B: 3-(1H-pyrrolol-2,3-b]pyridin-3-yl)-2,5-pyrrolidinedione

[0152] A mixture of the compound obtained in the above Step (0.327 mmol)and a catalytic amount of 10% palladium-on-carbon in methanol (40 ml) ishydrogenated at one atmosphere for 24 hours. The mixture is filteredover Celite and the expected product is obtained after purification ofthe residue by chromatography on silica gel using ethyl acetate aseluant.

[0153] Step C: 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrole-2,5-dione

[0154] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

PREPARATION F1-methyl-3-[1-(2,3,4,6-tetra-O-acetyl-β-D-glueopyranosyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione

[0155] Step A:3-bromo-1-methyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrole-2,5-dione

[0156] The expected product is obtained in accordance with the proceduredescribed in Step A of Preparation E, usingN-methyl-2,3-dibromomaleimide as substrate.

[0157] Melting point: 158° C.

[0158] Step B:3-bromo-1-methyl-4-[1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1-H-pyrrole-2,5-dione

[0159] 2,3,4,6-Tetra-O-acetylglucopyranose (1.95 mmol) andtriphenylphosphine (1.95 mmol) are added dropwise to a solution of thecompound of the above Step (0.927 mmol) dissolved in 40 ml of drytetrahydrofuran. The temperature is slowly brought back to ambienttemperature, and then the reacton mixture is stirred for a further 15hours. Following hydrolysis, the organic product is extracted with ethylacetate. The organic phases are combined, dried over magnesium sulphateand filtered, and the solvent is evaporated off. The expected product isobtained after purification by chromatography on silica gel.

[0160] Step C:1-methyl-3-[1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-2,5-pyrrolidinedione

[0161] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation E, starting from the compound of theabove Step.

[0162] Step D:1-methyl-3-[1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione

[0163] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

PREPARATION G1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrole-2,5-dione

[0164] Step A:1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,5-pyrrolidinedione

[0165] A mixture of the compound obtained in Step A of Preparation F(0.65 mmol) and 10% palladium-on-carbon (20 mg) in methanol (40 ml) ishydrogenated at 1 atmosphere for 3.5 hours. The mixture is filtered overCelite. The filtrate is evaporated off and the expected product isobtained after purification of the residue by flash chromatography onsilica gel (AcOEt then AcOEt/MeOH 9:1).

[0166] Melting point: 199-202° C.

[0167] IR (KBr): ν_(C═O)=1690, 1770 cm⁻¹; ν_(NH)=3250-3500 cm⁻¹.

[0168] Step B:1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrole-2,5-dione

[0169] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

[0170] Melting point: >250° C.

[0171] IR (KBr): ν_(C═O)=1700, 1760 cm⁻¹; ν_(NH)=3300-3600 cm⁻¹.

PREPARATION H 3-[5-(benzyloxy)-1H-indol-3-yl]-1H-pyrrole-2,5-dione

[0172] Step A: 3-[5-(benzyloxy)-1H-indol-3-yl]-2,5-pyrrolidinedione

[0173] The expected product is obtained in accordance with the proceduredescribed in Step A of Preparation C, with the replacement ofN-methylmaleimide by maleimide.

[0174] Melting point: 175° C.

[0175] IR (KBr) ν_(C═O)=1690, 1780 cm⁻¹; ν_(NH)=3210-3320 cm⁻¹.

[0176] Step B: 3-[5-(benzyloxy)-1H-indol-3-yl]-1H-pyrrole-2,5-dione

[0177] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

[0178] Melting point: 211° C.

[0179] IR (KBr): ν_(C═C)=1600 cm⁻¹; ν_(C═O)=1705, 1755cm⁻¹;ν_(NH)=3150-3450 cm⁻¹.

PREPARATION I 3-(5-bromo-1H-indol-3-yl)-1H-pyrrole-2,5-dione

[0180] Step A: 3-(5-bromo-1H-indol-3-yl)-2,5-pyrrolidinedione

[0181] The expected product is obtained in accordance with the proceduredescribed in Step A of Preparation C, with the replacement ofN-methylmaleimide by maleimide and of 5-benzyloxy-indole by5-bromo-indole.

[0182] Melting point: 208-215° C.

[0183] IR (KBr): ν_(C═O)=1700, 1755 cm⁻¹; ν_(NH)=3450 cm⁻¹.

[0184] Step B: 3-(5-bromo-1H-indol-3-yl)-1H-pyrrole-2,5-dione

[0185] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

[0186] Melting point: 268° C.

[0187] IR (KBr): ν_(C═C)=1595 cm⁻¹; ν_(C═O)=1705, 1750 cm⁻¹;ν_(NH)=3200-3340 cm⁻¹.

PREPARATION J 3-(5-chloro-1H-indol-3-yl)-1H-pyrrole-2,5-dione

[0188] Step A: 3-(5-chloro-1H-indol-3-yl)-2,5-pyrrolidinedione

[0189] The expected product is obtained in accordance with the proceduredescribed in Step A of Preparation I, with the replacement of5-bromo-indole by 5-chloro-indole.

[0190] IR (KBr): ν_(C═O)=1700, 1780 cm⁻¹; ν_(NH)=3200-3500 cm⁻¹.

[0191] Step B: 3-(5-chloro-1H-indol-3-yl)-1H-pyrrole-2,5-dione

[0192] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

[0193] Melting point: 254-264° C.

[0194] IR (KBr): ν_(C═C)=1605 cm⁻¹; ν_(C═O)=1710, 1750 cm⁻¹;ν_(NH)=3100-3350 cm⁻¹.

PREPARATION K 3-(5-fluoro-1H-indol-3-yl)-1H-pyrrole-2,5-dione

[0195] Step A: 3-(5-fluoro-1H-indol-3-yl)-2,5-pyrrolidinedione

[0196] The expected product is obtained in accordance with the proceduredescribed in Step A of Preparation I, with the replacement of5-bromo-indole by 5-fluoro-indole.

[0197] Melting point: 190-195° C.

[0198] IR (KBr): ν_(C═C)=1690, 1775 cm⁻¹; ν_(NH)=3360 cm⁻¹.

[0199] Step B: 3-(5-fluoro-1H-indol-3-yl)-1H-pyrrole-2,5-dione

[0200] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

[0201] Melting point: 255-265° C.

[0202] IR (KBr) ν_(C═C)=1605 cm⁻¹; ν_(C═O)=1720, 1750 cm⁻¹;ν_(NH)=3150-3350 cm⁻¹.

PREPARATION L 3-(5-hydroxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione

[0203] Step A: 3-(5-hydroxy-1H-indol-3-yl)-2,5-pyrrolidinedione 10%palladium-on-carbon (135 mg) is added to a solution of the compound ofStep A of Preparation H (450 mg) in dry methanol (90 ml). After havingpurged in vacuo for 20 minutes, the reaction mixture is placed under ahydrogen atmosphere (1 atm) for 3 hours. Following filtration overCelite and evaporation of the filtrate, the expected product isobtained.

[0204] IR (film): ν_(C═C)=1700 cm⁻¹; ν_(NH,OH)=3000-3700 cm⁻¹.

[0205] Step B: 3-(5-hydroxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione

[0206] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

[0207] Melting point: 292-298° C.

[0208] IR (KBr) ν_(C═C)=1610 cm⁻¹; ν_(C═O)=1690, 1760 cm⁻¹;ν_(NH,OH)=3260, 3370, 3430 cm⁻¹.

PREPARATION M3-[1-(2,3,4,6-tetra-O-benzyl-β-D-glueopyranosyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione

[0209] Step A: 3-bromo-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione

[0210] A solution of 1.445 g of indole dissolved in 29 ml of drytetrahydrofliran is brought to from −20 to −10° C. under argon, and then26 ml of LiHMDS (1M in hexane) are added dropwise in the course of 15minutes. After 45 minutes at −10° C., the solution is diluted with anadditional 15 ml of tetrahydrofuran and a solution of 2 g ofN-methyl-2,3-dibromomaleimide dissolved in 17 ml of tetrahydrofuran isadded dropwise in the course of 30 minutes. After 15 minutes at −10° C.and 15 minutes at 0° C., the reaction is stopped by the addition, at 0°C., of 50 ml of a 0.3N hydrochloric acid solution. The reaction mixtureis extracted with ethyl acetate, and the organic phases are washed witha saturated NaCl solution, dried over MgSO₄ and then evaporated underreduced pressure. The desired product is precipitated using methanol.

[0211] Melting point=167-168° C.

[0212] Step B:3-bromo-1-methyl-4-[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-H-indol-3-yl]-1H-pyrrole-2,5-dione

[0213] A solution of the compound of the above Step A, PPh₃ (3 equiv.)and 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl (3 equiv.) in dry THF iscooled to −78° C. DIAD (3 equiv.) is then added dropwise. The reactionmixture is stirred for 4 hours, while allowing to warm up again toambient temperature. A 0.2M solution of HCl is poured in and the mixtureis extracted with ethyl acetate. The organic phase is washed insuccession with a saturated aqueous NaHCO₃ solution and with water andthen dried over MgSO₄. After filtration and removal of the solvent byevaporation, and chromatography on silica gel (toluene/ethyl acetate:50/1), the expected product is obtained.

[0214] Melting point: 55° C.

[0215] IR (KBr): ν_(C═C)=1640 cm⁻¹; ν_(C═O)=1710, 1770 cm⁻¹;ν_(NH,OH)=3200-3600 cm⁻¹.

[0216] Step C:1-tmethyl-3-[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1H-indol-3-yl]2,5-pyrrolidinedione

[0217] A solution of the compound of the above Step B in methanol anddry THF is hydrogenated (1 atm.) for 3 hours in the presence of 10%palladium-on-carbon and pyridine (0.5 equiv.). Following filtration overCelite and evaporation of the filtrate, and chromatography on silica gel(cyclohexane/ethyl acetate), the expected product is obtained.

[0218] Step D:1-methyl-3-[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione

[0219] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

[0220] Step E:3-[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione

[0221] A mixture of the compound of the above Step D and NaOH indistilled water is heated at reflux for 2 hours. After cooling,concentrated hydrochloric acid is poured in dropwise until a yellowprecipitate is formed. The yellow solid is filtered off over a frit andwashed with water, yielding the desired anhydride, which is then treatedwith a solution of ammonium hydroxide in THF to yield the expectedcompound.

PREPARATION N3-{[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)]-1H-pyrrolo[2,3-b]pyridin-3-yl{-1H-pyrrole-2,5-dione

[0222] Step A:3-bromo-1-methyl-4-[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2,5-dione

[0223] 2,3,4,6-O-benzylglucopyranosyl (264 mg) and triphenylphosphine(128 mg) are added to a solution of the compound of Step A ofPreparation G (50 mg) dissolved in 4 ml of dry THF. The reaction mixtureis cooled to −78° C., and then DIALD (97 μl) is added dropwise. Thetemperature is slowly brought back to ambient temperature and then thereaction mixture is stirred for a further 15 hours. Following hydrolysis(40 ml of water), the organic product is extracted with ethyl acetate(3×150 ml). The organic phases are combined, dried over magnesiumsulphate and filtered, and the solvent is evaporated off. Purificationby chromatography on silica gel (cyclohexane/ethyl acetate: 8/2 to 7/3)allows the expected product to be isolated.

[0224] IR (KBr): ν_(C═O)=1710, 1740, 1760 cm⁻¹.

[0225] Step B:1-methyl-3-[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-2,5-pyrrolidinedione

[0226] NaHCO₃ (66 mg) and 10% Pd/C (65 mg) are added to a suspension ofthe compound of the above Step A (65 mg) in 10 ml of ethyl acetate. Themixture is placed under a hydrogen atmosphere (1 bar) at ambienttemperature for 24 hours. Filtration over Celite allows the catalyst tobe removed and the filtrate is evaporated under reduced pressure.Purification by flash chromatography on silica gel (cyclohexane/ethylacetate: 8/2 to 7/3) allows the expected product to be isolated.

[0227] IR (KBr): ν_(C═O)=1710-1750 cm⁻¹.

[0228] Step C:1-methyl-3-{[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)]-1H-pyrrolo[2,3-b]pyridin-3-yl{-1H-pyrrole-2,5-dione

[0229] The expected product is obtained in accordance with the proceduredescribed in Step B of Preparation C, starting from the compound of theabove Step.

[0230] Step D:3-{[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)]-1H-pyrrolo[2,3-pyridin-3-yl}-2,5-furandione

[0231] NaOH pellets (14 mmol) and THF are added to a suspension of thecompound of the above Step C (1 mmol) in water. The mixture is stirredat ambient temperature for 2 hours, and is then acidified to pH 1 by theaddition of concentrated hydrochloric acid. After stirring for 30minutes, the organic product is extracted with ethyl acetate (3×150 ml).The organic phases are combined, dried over magnesium sulphate andfiltered, and the solvent is evaporated off. Purification bychromatography on silica gel allows the expected product to be isolated.

[0232] Step E:3-{[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)]-1H-pyrrolo[2,3-b]pyridin-3-yl}-1H-pyrrole-2,5-dione

[0233] In a sealed tube, a solution of the compound of the above Step Din THF is added to a solution of THF saturated with NH₃. The reactionmixture is stirred at 80° C. for 18 hours. After cooling, the mixture ispoured into water and extracted repeatedly with ethyl acetate. Theorganic phases are combined, dried over magnesium sulphate and filtered,and the solvent is evaporated off. Purification by chromatography onsilica gel allows the expected product to be isolated.

[0234] The compounds of Preparations O to AP are obtained according tothe procedure of Preparation C, starting from the appropriate indolesand with the replacement of N-methylmaleimide by maleimide.

PREPARATION O 3-(5-amino-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATIONP 3-(4-amino-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION O3-(5,6-dimethoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION R3-(4-nitro-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION S3-(4-fluoro-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION T3-(6-fluoro-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION U3-(4-hydroxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION V3-(5-hydroxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION W3-(4-methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION X3-(5-methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION Y3-(6methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION Z3-(7-methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AA3-(4-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AB3-(5-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AC3-(6methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AD3-(7-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AE3-(4-chloro-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AF3-(5-chloro-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AG3-(6chloro-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AH3-(7-chloro-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AI3-(4-bromo-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AJ3-(6-bromo-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AK3-(7-bromo-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AL3-(5-methoxy-4-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione PREPARATION AM3-1(7-(benzyloxy)1H-indol-3-yl]-1H-pyrrole-2,5-dione PREPARATION AN3-16-(benzyloxy)-1H-indol-3-yl]-1H-pyrrole-2,5-dione PREPARATION AO3-[5-(benzyloxy)-6-methoxy-1H-indol-3-yl]-1H-pyrrole-2,5-dionePREPARATION AP 3-(1-methyl-1H-indol-3-yl]-1H-pyrrole-2,5-dione. EXAMPLE1 1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0235] The compound of Preparation A (0.388 mmol) is heated at refluxfor 24 hours in 24 ml of dioxane in the presence of trifluoroacetic acid(400 μl). After removal of the solvent by evaporation, the crystals aretaken up in ethyl acetate and washed with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution. Theexpected product is obtained by filtration of the crystals over a frit.

[0236] Melting point: >300° C.

[0237] IR (KBr): ν_(C═O)=1690, 1730, 1745, 1780 cm⁻¹; ν_(NH)=3280-3380cm¹.

[0238] Mass spectrometry (FAB): 306.05 [M+H⁺].

EXAMPLE 22,5-dimethyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0239] A mixture of the compound of Preparation B (1 mmol) andN-methylmaleimide (1.10 mmol) in 17 ml of para-xylene is refluxed for 24hours. After cooling, the yellow precipitate is filtered off and thenwashed with para-xylene. Chromatography on a silica column (ethylacetate/cyclohexane: 1/1; ethyl acetate; ethyl acetate/methanol: 98/2)allows a mixture of isomers to be obtained which is heated at reflux for84 hours in 25 ml of dioxane in the presence of trifluoroacetic acid.After removal of the solvent by evaporation, the crystals are taken upin ethyl acetate and washed with a saturated sodium hydrogen carbonatesolution and a saturated sodium chloride solution. The expected productis obtained by filtration of the crystals over a frit.

[0240] Melting point: >300° C.

[0241] IR (KBr): ν_(C═O)1695, 1720 cm⁻¹; ν_(NH)=3410 cm⁻¹.

[0242] Mass spectrometry (FAB): 334.08 [M+H⁺].

EXAMPLE 32-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0243] The expected product is obtained in accordance with the proceduredescribed in Example 2, starting from the compound of Preparation B andmaleimide.

[0244] Melting point: >300° C.

[0245] IR (KBr): ν_(C═O)=1710, 1720, 1760, 1780 cm⁻¹; ν_(NH)=3260-3395cm⁻¹.

[0246] Mass spectrometry (FAB): 320.06 [M+H⁺].

EXAMPLE 410(benzyloxy)-2,5-dimethyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0247] The expected product is obtained in accordance with the proceduredescribed in Example 2, starting from the compound of Preparation C andN-methylmaleimide.

[0248] Melting point: >300° C.

[0249] IR (KBr): ν_(C═O)=1700, 1720, 1775 cm⁻¹; ν_(NH)=3480 cm⁻¹;

[0250] Mass spectrometry (FAB): 440.12 [M+H⁺].

EXAMPLE 55-methylfuro[3,4-c]pyrrolo[3,4-a]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0251] The expected product is obtained in accordance with the proceduredescribed in, Example 2, starting from the compound of Preparation D andN-methylmaleimide.

[0252] Melting point: 294° C. (decomposition).

[0253] IR (KBr) ν_(C═O)=1775, 1840 cm⁻¹; ν_(NH)=3370 cm⁻¹.

[0254] Mass spectrometry (FAB): 321.05 [M+H⁺].

EXAMPLE 62-[2-(diethylamino)ethyl]-5-methyl-1H-dipyrrolo[13,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetronehydrochloride

[0255] N-N-diethylethylenediamine (0.132 mmol) is added dropwise to asolution of the compound of Example 5 (0.088 mmol) dissolved in 5.2 mlof anhydrous tetrahydrofuran. The mixture is heated at 65° C. for 4 dayswith the exclusion of light and then cooled and taken up in a mixture ofan aqueous 1N hydrochloric acid solution (40 ml) and ethyl acetate. Theorganic product is extracted with ethyl acetate. The aqueous phase istaken up in ethyl acetate and the pH is adjusted to 12 by the additionof a,saturated aqueous sodium hydrogen carbonate solution. The organicproduct is extracted with ethyl acetate. The organic phases arecombined, dried over magnesium sulphate and filtered, and the solvent isevaporated off in the cold. To a solution, cooled to 0° C., of the amineso obtained dissolved in 400 μl of methanol there is added dropwise anaqueous 1N hydrochloric acid solution (190 μl). The mixture is, stirredfor 30 minutes. The solvent is evaporated off, allowing the expectedproduct to be isolated.

[0256] Melting point: 184° C. (decomposition).

[0257] IR (KBr): ν_(C═O)=1710, 1720, 1765, 1775 cm⁻¹; ν_(NH)=3300-3600cm⁻¹.

[0258] Mass spectrometry (FAB): 419.17 [M+H⁺].

EXAMPLE 71H-pyrido[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6(2H,5H,7H)-tetrone

[0259] The expected product is obtained in accordance with the proceduredescribed in Example 2, starting from the compound of Preparation E andmaleimide.

EXAMPLE 82-methyl-7-(2,3,4,6tetra-O-acetyl-β-D-glucopyranosyl)-1H-pyrido[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6(2H,5H,7H)-tetrone

[0260] The expected product is obtained in accordance with the proceduredescribed in Example 2, starting from the compound of Preparation F andmaleimide.

EXAMPLE 92-methyl-1H-pyrido[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6(2H,5H,7H)-tetrone

[0261] A mixture of the compound of Preparation G (55.0 mg) andmaleimide (25.9 mg) in xylene (5 ml) is heated at reflux for 20 hours.After cooling, the mixture is filtered and washed with xylene. The solidobtained (70.8 mg) is heated at reflux for 3 days in dioxane (5 ml) inthe presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (115.5 mg).After removal of the solvent by evaporation, the residue is taken up inwater and the solid obtained is filtered off and washed with water andethyl acetate, allowing the expected product to be obtained.

[0262] Melting point: >300° C.

[0263] IR (KBr): ν_(C═C)=1600 cm⁻¹; ν_(C═O)=1710, 1730, 1770, 1780 cm⁻¹;ν_(NH)=3200 cm⁻¹.

EXAMPLE 102-methylfuro[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,6(2H,7H)-tetrone

[0264] A mixture of the compound of Preparation B (315 mg) and maleicanhydride (164 mg) in p-xylene (24 ml) is heated at reflux for 40 hours.After returning to ambient temperature, the mixture is filtered and thecrystals are washed with p-xylene and then dried. The solid obtained(357 mg) is heated at reflux in dioxane (8 ml) for 3 days in thepresence of 2,3dichloro-5,6-dicyano-1,4-benzoquinone (540 mg). Afterreturning to ambient temperature, water and with ethyl acetate areadded. The solid at the interface is filtered off over a frit and washedwith water and ethyl acetate, allowing the expected product to beisolated.

[0265] Melting point: >300° C.

[0266] IR (KBr): ν_(C═O)=1705, 1760, 1835 cm⁻¹; ν_(NH)=3770 cm⁻¹.

EXAMPLE 115-[2-(diethylamino)ethyl]-2-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetronehydrochloride

[0267] N-N-diethylethylenediamine (20 μl) is added dropwise to asolution of the compound of Example 10 in dry tetrahydrofuran (5.5 ml).The mixture is heated at 65° C. for 4 days with the exclusion of light.After returning to ambient temperature, the mixture is evaporated todryness, taken up in 1 ml of acetic anhydride in the presence of AcONa(75 mg) and then heated at 90° C. for 4 hours. The crude reactionmixture is cooled and then taken up in a mixture of an aqueous 1Nhydrochloric acid solution (40 ml) and ethyl acetate. The aqueous phaseis then taken up in ethyl acetate and treated with an aqueous saturatedsodium hydrogen carbonate solution. The organic product is thenextracted with ethyl acetate (3×50 ml). The organic phases are combinedand dried over magnesium sulphate and the solvent is evaporated off atroom temperature. The free amine so obtained (32.8 mg) is taken up inmethanol (1 ml) and then cooled to 0° C. An aqueous 1N hydrochloric acidsolution (172 μl) is then added dropwise. The mixture is stirred for 30minutes. The solvent is evaporated off, allowing the expected product tobe obtained.

[0268] Melting point:=278-280° C.

[0269] IR (KBr): ν_(C═O)=1710, 1770 cm⁻¹; ν_(NH)=3200, 3600 cm⁻¹.

EXAMPLE 125-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0270] The expected product is obtained in accordance with the proceduredescribed in Example 9, starting from the compound of Preparation A andwith the replacement of maleimide by N-methylmaleimide.

[0271] Melting point: >300° C.

[0272] IR (KBr): ν_(C═O)=1695, 1725, 1765, 1775 cm⁻¹ν_(NH)=3220, 3330cm⁻¹.

EXAMPLE 13 Furo[3,4-a[pyrrrolo[3,4-c]carbazole-1,3,4,6(2H,7H)-tetrone

[0273] The expected product is obtained in accordance with the proceduredescribed in Example 10, starting from the compound of Preparation A.

[0274] Melting point: >300° C.

[0275] IR (KBr): ν_(C═C)=1610 cm⁻¹; ν_(C═O)=1700-1850 cm⁻¹; ν_(NH)=3240,3380 cm⁻¹.

EXAMPLE 1410-(benzyloxy)-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0276] The expected product is obtained in accordance with the proceduredescribed in Example 9, starting from the compound of Preparation H.

[0277] Melting point: >300° C.

[0278] IR (KBr): ν_(C═O)=1725, 1755, 1780 cm⁻¹; ν_(NH)=3150-3500 cm⁻¹.

EXAMPLE 15 10-bromo-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0279] The expected product is obtained in accordance with the proceduredescribed in Example 9, starting from the compound of Preparation I.

[0280] Melting point: >300° C.

[0281] IR (KBr): ν_(C═C)=1600 cm⁻¹; ν_(C═O)=1710, 1720, 1760 cm⁻¹;ν_(NH)=3150-3350 cm⁻¹;

EXAMPLE 1610-chloro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0282] The expected product is obtained in accordance with the proceduredescribed in Example 9, starting from the compound of Preparation J.

[0283] Melting point: >300° C.

[0284] IR (KBr): ν_(C═C)=1600 cm⁻¹; ν_(C═O)=1710, 1720, 1760 cm⁻¹;ν_(NH)=3120-3380 cm⁻¹.

EXAMPLE 1710-fluoro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0285] The expected product is obtained in accordance with the proceduredescribed in Example 9, starting from the compound of Preparation K.

[0286] Melting point: >300° C.

[0287] IR (KBr): ν_(V═O)=1710, 1780cm⁻¹;ν_(NH)=3100-3350cm⁻¹.

EXAMPLE 1810-hydroxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0288] The expected product is obtained in accordance with the proceduredescribed in Example 9, starting from the compound of Preparation L.

[0289] Melting point: >300° C.

[0290] IR (KBr): ν_(C═O)=1725, 1770 cm⁻¹; ν_(NH)=3100-3650 cm⁻¹.

EXAMPLE 197-[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)]-1H-dipyrrolo[3,4a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0291] The expected product is obtained in accordance with the proceduredescribed in Example 2, starting from the compound of Preparation M andmaleimide.

EXAMPLE 207-(β-D-glucopyranosyl)-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0292] Debenzylation by BBr₃ of the compound of Example 19 indichloromethane allows the expected compound to be obtained.

EXAMPLE 217-[1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)]-1H-pyrido[2,3-b]dipyrrolo[3,4-e:3,4-g]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0293] The expected product is obtained in accordance with the proceduredescribed in Example 9, starting from the compound of Preparation N.

EXAMPLE 227-(β-D-glueopyranosyl)]-1H-pyrido[2,3-b]dipyrrolo[3,4-e:3,4-g]-indole-1,3,4,6(2H,5H,7H)-tetrone

[0294] A 1M solution of BBr₃ in CH₂Cl₂ (8 eq.) is added to a solution ofthe compound of Example 21 in dichloromethane at −78° C. After 10minutes′stirring at −78° C., the reaction mixture is hydrolysed andbrought to ambient temperature, and then extracted repeatedly with ethylacetate. The organic phase is dried over magnesium sulphate and thenconcentrated under reduced pressure. Chromatography on silica gel allowsthe expected product to be isolated.

[0295] The products of Examples 23 to 50 are obtained according to theprocedure described in Example 9, starting from the compounds ofPreparations 0 to AP, respectively.

EXAMPLE 2310-amino-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 2411-amino-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 259,10-dimethoxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 2611-nitro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 2711-fluoro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 289-fluoro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 2911-hydroxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 3010-hydroxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 3111-methoxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 3210-methoxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 339-methoxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 348-methoxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 3511-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 3610-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 379-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 388-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 3911-chloro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone.EXAMPLE 4010-chloro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 419-chloro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7,H)-tetroneEXAMPLE 428-chloro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 4311-bromo-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 449-bromo-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 458-bromo-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 4610-metboxy-11-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 478-(benzyloxy)-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 489-(benzyloxy)-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 4910-(benzyloxy)-9-methoxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 507-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetroneEXAMPLE 512-hydroxy-5-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetron

[0296] The expected product is obtained in accordance with the proceduredescribed in Example 6, with the replacement ofN,N-diethylethylenediamine by hydroxylamine.

EXAMPLE 522-amino-5-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0297] The expected product is obtained in accordance with the proceduredescribed in Example 6, with the replacement ofN,N-diethylethylenediamine by hydrazine.

EXAMPLE 532-(dimethylamino)-5-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0298] The expected product is obtained in accordance with the proceduredescribed in Example 6, with the replacement ofN,N-diethylethylenediamine by 1,1-dimethylhydrazine.

EXAMPLE 542-(3-hydroxypropyl)-5-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone

[0299] The expected product is obtained in accordance with the proceduredescribed in Example 6, with the replacement ofN,N-diethylethylenediamine by 3-amino-1-propanol.

EXAMPLE 552-(3-methoxypropyl)-5-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetronte

[0300] The expected product is obtained in accordance with the proceduredescribed in Example 6, with the replacement ofN,N-diethylethylenediamine by 3-methoxypropylamine.

PHARMA COLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE 56 InVitro Activity

[0301] Three cell lines were used:

[0302] L1210 murine leukaemia

[0303] A549 non-small-cell human lung carcinoma

[0304] DU145 prostate carcinoma

[0305] L1210 murine leukaemia was used in vitro. The cells are culturedin RPMI 1640 complete culture medium containing 10% foetal calf serum, 2mM glutamine, 50 units/ml of penicillin, 50 μg/ml of streptomycin and 10mM Hepes, pH: 7.4. The cells are distributed on microplates and areexposed to the cytotoxic compounds for 4 doubling periods, or 48 hours.The number of viable cells is then quantified by a colorimetric assay,the Microculture Tetrazolium Assay (J. Carmichael et al., Cancer Res.;47, 936-942 (1987)). The results are expressed as the IC₅₀, theconcentration of cytotoxic agent that inhibits the proliferation of thetreated cells by 50%. By way of example, the compound of Example 2exhibits IC₅₀ values of 6.8 μM on L1210, 4.7 μM on A549 and 5.4 μM on DU145.

EXAMPLE 57 Pharmaceutical Composition: Injectable Solution

[0306] Compound of Example 1 . . . 10 mg

[0307] Distilled water for injectable preparations . . . 25 ml

1- A compound selected from those of formula (I):

wherein: A represents a saturated or partially or fully unsaturatedring, wherein the unsaturation optionally confers an aromatic nature onthe ring, W₁, together with the carbon atoms to which it is bonded,represents phenyl or pyridyl, Z represents one or more identical ordifferent groups of formula U—V wherein: U represents single bond,linear or branched (C₁-C₆)alkylene, linear or branched (C₂-C₆)alkenyloptionally substituted by one or more identical or different groupsselected from halogen and hydroxy, and/or optionally containing one ormore unsaturated bonds, V represents a group selected from hydrogen,halogen, cyano, nitro, azido, linear or branched (C₁-C₆)alkyl, aryl,aryl-(C₁-C₆)alkyl in which the alkyl moiety may be linear or branched,hydroxy, linear or branched (C₁-C₆)alkoxy, aryloxy, aryl-(C₁-C₆)alkoxyin which the alkoxy moiety may be linear or branched, formyl, carboxy,aminocarbonyl, NR₃R₄, —C(O)—T₁, —C(O)—NR₃—T₁, —NR₃—C(O)—T₁, —O—C(O)—T₁,—C(O)O—T₁, —NR₃—T₂—NR₃R₄, —NR₃—T₂—OR₃, —NR₃—T₂—CO₂R₃, —O—T′₂—NR₃R₄,—O—T′₂—OR₃, —O—T′₂—CO₂R₃, and —S(O)_(t)—R₃, wherein: R₃ and R₄, whichmay be indentical or different, each represents a group selected fromhydrogen, linear or branched (C₁-C₆)alkyl, aryl, and aryl-(C₁-C₆)alkylin which the alkyl moiety may be linear or branched, or R₃+R₄, with thenitrogen atom carrying them, together form a saturated monocyclic orbicyclic heterocycle that has from 5 to 10 ring atoms, optionallycontains in the ring system a second hetero atom selected from oxygenand nitrogen, and is optionally substituted by a group selected fromlinear or branched (C₁-C₆)alkyl, aryl, aryl-(C₁-C₆)alkyl in which thealkyl moiety may be linear or branched, hydroxy, linear or branched(C₁-C₆)alkoxy, amino, linear or branched mono(C₁-C₆)alkylamino, anddi(C₁-C₆)alkylamino in which the alkyl moieties may be linear orbranched, T₁ represents a group selected from linear or branched(C₁-C₆)alkyl that is optionally substituted by a group selected from—OR₃, —NR₃R₄, —CO₂R₃, —C(O)R₃ and —C(O)NR₃R₄ wherein R₃ and R₄ are asdefined hereinbefore; aryl, and aryl(C₁-C₆)alkyl in which the alkylmoiety may be linear or branched; or T₁ represents linear or branched(C₂-C₆)alkenyl optionally substituted by a group selected from —OR₃,—NR₃R₄, —CO₂R₃, —C(O)R₃ and —C(O)NR₃R₄ wherein R₃ and R₄ are as definedhereinbefore, T₂ represents linear or branched (C₁-C₆)alkylene, T′₂represents or a linear or branched (C₁-C₆)alkylene optionallysubstituted with one ore more hydroxy groups, t represents integer offrom 0 to 2 inclusive, or Z represents methylenedioxy or ethylenedioxy,Q₁ represents a group selected from oxygen, NR₂ wherein R₂ represents agroup selected from hydrogen, linear or branched (C₁-C₆)alkyl, aryl,aryl-(C₁-C₆)alkyl in which the alkyl moiety may be linear or branched,cycloalkyl, cycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety may belinear or branched, —OR₃, —NR₃R₄, —O—T₂—NR₃R₄, —NR₃—T₂—NR₃R₄, linear orbranched (C₁-C₆)hydroxyalkylamino, di((C₁-C₆)hydroxyalkyl)amino in whichthe alkyl moieties may be linear or branched, —C(O)—R₃ and —NH—C(O)—R₃;or R₂ represents linear or branched (C₁-C₆)alkylene substituted by oneor more identical or different groups selected from halogen, cyano,nitro, —OR₃, —NR₃R₄, —CO₂R₃, —C(O)R₃, linear or branched(C₁-C₆)hydroxyalkylamino di((C₁-C₆)hydroxyalkyl)amino in which the alkylmoieties may be linear or branched, and —C(O)—NHR₃, R₃, R₄ and T₂ beingas defined hereinbefore, Q₂ represents a group selected from oxygen,NR′₂ wherein R′₂ represents a group selected from hydrogen, linear orbranched (C₁-C₆)alkyl, aryl, aryl-(C₁-C₆)alkyl in which the alkyl moietymay be linear or branched, cycloalkyl, cycloalkyl-(C₁-C₆)alkyl in whichthe alkyl moiety may be linear or branched, —OR₃, —NR₃R₄, —O—T₂—NR₃R₄,—NR₃—T₂—NR₃R₄, linear or branched (C₁-C₆)hydroxyalkylamino,di((C₁-C₆)hydroxyalkyl)amino in which the alkyl moieties may be linearor branched, —C(O)—R₃ and —NH—C(O)—R₃; or R′₂ represents a linear orbranched (C₁-C₆)alkylene substituted by one or more identical ordifferent groups selected from halogen, cyano, nitro, —OR₃, —NR₃R₄,—CO₂R₃, —C(O)R₃, linear or branched (C₁-C₆)hydroxyalkylamino,di((C₁-C₆)hydroxyalkyl)amino in which the alkyl moieties may be linearor branched, and —C(O)—NHR₃, R₃, R₄ and T₂ being as definedhereinbefore, X₁ represents a group selected from hydrogen, hydroxy,linear or branched (C₁-C₆)alkoxy, mercapto, and linear or branched(C₁-C₆)alkylthio, Y₁ represents hydrogen, or X₁ and Y₁, with carboncarrying them, together form carbonyl or thiocarbonyl, X₂ represents agroup selected from hydrogen, hydroxy, linear or branched (C₁-C₆)alkoxy,mercapto and linear or branched (C₁-C₆)alkylthio, Y₂ representshydrogen, or X₂ and Y₂, with carbon carrying them, together formcarbonyl or thiocarbonyl, X′₁ represents a group selected from hydrogen,hydroxy, linear or branched (C₁-C₆)alkoxy, mercapto and linear orbranched (C₁-C₆)alkylthio, Y′₁ represents hydrogen, or X′₁ and Y′₁, withcarbon carrying them, together form carbonyl or thiocarbonyl, X′₂represents a group selected from hydrogen, hydroxy, linear or branched(C₁-C₆)alkoxy, mercapto and linear or branched (C₁-C₆)alkylthio, Y′₂represents hydrogen, or X′₂ and Y′₂, with carbon carrying them, togetherform carbonyl or thiocarbonyl, R₁ represents a group selected fromhydrogen, linear or branched (C₁-C₆)alkyl that is optionally substitutedby one or more groups selected from hydroxy, linear or branched(C₁-C₆)alkoxy, linear or branched (C₁-C₆)hydroxyalkoxy or NR₃R₄, thegroups R₃ and R₄ being as defined hereinbefore; or R₁ represents a groupof formula (a):

wherein: R_(a), R_(b), R_(c) and R_(d), which may be identical ordifferent, each represents, independently of the others, a bond or agroup selected from hydrogen, halogen, hydroxy, linear or branched(C₁-C₆)alkoxy, aryloxy, aryl-(C₁-C₆)alkoxy in which the alkoxy moietymay be linear or branched, linear or branched (C₁-C₆)alkyl,aryl-(C₁-C₆)alkyl in which the alkyl moiety may be linear or branched,aryl, —NR₃P4 wherein R₃ and R₄ are as defined hereinbefore, azido,—N═NR₃ (wherein R₃ is as defined hereinbefore), —O—C(O)—R₅ wherein R₅represents linear or branched (C₁-C₆)alkyl (optionally substituted byone or more groups selected from halogen, hydroxy, amino, linear orbranched (C₁-C₆)alkylamino, and di(C₁-C₆)alkylamino in which the alkylmoieties may be linear or branched); or R₅ represents aryl,aryl-(C₁-C₆)alkyl in which the alkyl moiety may be linear or branched,cycloalkyl or heterocycloalkyl, R_(e) represents methylene (H₂C═) or agroup of formula —U₁—R_(a) wherein U₁ represents single bond, methyleneand R_(a) is as defined hereinbefore, n is 0 or 1,  it being understoodthat the group of formula (a) is bonded to the nitrogen atom by R_(a),R_(b), R_(c), R_(d) or R_(e), 10 its enantiomers, diastereoisomers, andaddition salts thereof with a pharmaceutically acceptable acid or base, with the proviso that the compound may not be:3b,6a,6b,7-tetrahydro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,3aH,5H-tetrone;5-ethyl-3b,6a,6b,7-tetrahydro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,3aH,5H)-tetrone;3b,6a,7,11c-tetrahydro-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-(2H,3aH,5H)-tetrone;3b,6a,6b,7-tetrahydrofuro[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,6-(2H,3aH,5H)-tetrone;wherein aryl is understood to mean a phenyl, naphthyl, dihydronaplthyl,tetrahydronaphthyl, indenyl or indanyl group, each of those groupsoptionally being substituted by one or more identical or differentgroups selected from halogen, linear or branched (C₁-C₆)alkyl, linear orbranched (C₁-C₆)trihaloalkyl, hydroxy, linear or branched (C₁-C₆)alkoxy,and NR₃R₄, R₃ and R₄ being as defined hereinbefore. 2- A compound ofclaim 1, wherein X₁ and Y₁, with carbon carrying them, together formcarbonyl, X₂ and Y₂, with carbon carrying them, together form carbonyl,X′₁ and Y′₁, with carbon carrying them, together form carbonyl and X′₂and Y′₂, with carbon carrying them, together form carbonyl. 3- Acompound of claim 1 wherein Q₁ represents —NR₂ wherein R₂ is as definedfor formula (I). 4- A compound of claim 1 wherein Q₂ represents —NR′₂wherein R′₂ is as defined for formula (I). 5- A compound of claim 1which is a compound of formula (IA):

wherein R₁, R₂, R′₂, W₁ and Z are as defined for formula (I). 6- Acompound of claim 1 which is a compound of formula (IB):

wherein R₁, R₂, R′₂ and Z are as defined for formula (I). 7- A compoundof claim 1 which is a compound of formula (IC):

wherein R₁, R₂, R′2 and Z area as defined for formula (I). 8- A compoundof claim 1 which is a compound of formula (ID):

wherein R₂, R′₂, W₁, Z, R_(b), R_(c), R_(d) and R_(e) are as defined forformula (I). 9- A compound of claim 1 which is a compound of formula(IE):

wherein R₂, R′₂, Z, R_(b), R_(c), R_(d) and R_(e) are as defined forformula (I). 10- A compound of claim 1 which is a compound of formula(IF):

wherein R₂, R′₂, Z, R_(b), R_(c), R_(d) and R_(e) are as defined forformula (I). 11- A compound of claim 1 wherein Z represents a group offormula U—V wherein U represents single bond and V represents a groupselected from hydrogen, halogen, nitro, linear or branched (C₁-C₆)alkyl,hydroxy, linear or branched (C₁-C₆)alkoxy, aryl-(C₁-C₆)alkoxy in whichthe alkoxy moiety may be linear or branched, NR₃R₄ wherein R₃ and R₄each represents a hydrogen atom. 12- A compound of claim 1 wherein Zrepresents a group of formula U—V wherein U represents single bond and Vrepresents a group selected from hydrogen, halogen, hydroxy,aryl-(C₁-C₆)alkoxy in which the alkoxy moiety may be linear or branched.13- A compound of claim 1 wherein R₁ represents hydrogen, linear orbranched (C₁-C₆)alkyl or a group of formula (a):

bonded to the nitrogen atom by Ra, wherein: R_(b), R_(c), and R_(d)represent hydroxy, aryl-(C₁-C₆)alkoxy in which the alkoxy moiety may belinear or branched, —O—C(O)—R₅ wherein R₅ represents linear or branched(C₁-C₆)alkyl, R_(e) represents a group of formula U₁—R_(a) wherein U₁represents methylene and R_(a) has the same definitions as R_(b), R_(c)and R_(d) and n is 0, 14- A compound of claim 1 wherein R₁ representshydrogen. 15- A compound of claim 1 wherein R₂ represents hydrogen,linear or branched (C₁-C₆)alkyl, OR₃, NR₃R₄, or linear or branched(C₁-C₆)alkylene substituted by OR₃, NR₃R₄ wherein R₃ and R₄ are asdefined for formula (I). 16- A compound of claim 1 wherein R₂ representshydrogen, linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)alkylene substituted by NR₃R₄ wherein R₃ and R₄ are as definedfor formula I. 17- A compound of claim 1 wherein R′₂ representshydrogen, linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)alkylene substituted by NR₃R₄ wherein R₃ and R₄ are as definedfor formula (I). 18- A compound of claim 1 which is selected from:1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone,2-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone,2,5-dimethyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone,2-[2-(diethylamino)ethyl]-5-methyl-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone,10-hydroxy-1H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6(2H,5H,7H)-tetrone,19- A method for treating a living body afflicted with cancer comprisingthe step of administering to the living body an amount of a compound ofclaim 1, which is effective for alleviation of said cancer 20- Apharmaceutical composition useful in treating cancer comprising asactive principle an effective amount of a compound as claimed in claim1, together with one or more pharmaceutically acceptable excipients orvehicles.